Work on this project will continue to proceed on three fronts: 1. Activation and expression of allograft immunity. It is now established that a metabolically active stimulator cell (the antigen presenting cell) is a major source of tissue immunogenicity. However, there is still uncertainty concerning the mechanism whereby alloantigen bearing S+ cells activate CD8 T cells; the CD8 cell we have shown to mediate islet allograft rejection in vivo. Work in this area will investigate the potential of different cytokines to act a costimulators for the CD8 T cell, and the conditions of antigen presentation that influence the expression of costimulator activity by active cytokines. At the level of expression of allograft immunity, progress has been made in defining the role of lymphokines in the effector function of CD8 cells in vivo. Preliminary data using cloned CD8 T cells has focused attention on the role of gamma-IFN in this process. The involvement of this lymphokine in the rejection process will be examined in more detail during the forthcoming grant period. 2. Tolerance induction in adult animals. We have now established that cultured islet allografts following transplantation induce a suppressive form of tolerance in the recipient animal. Apart from knowing what this tolerance is mediated by some form of suppression rather than clonal deletion, we have no further information on the detailed mechanisms mediating this suppression. This portion of the grant will investigate the role of cellular and humoral components in the mediation of this suppressor form of tolerance. 3. Disease recurrence in islets transplanted to spontaneously diabetic animals. Islet tissue grafted to spontaneously diabetic allogeneic recipients is under threat of disease recurrence. This process is mediated by CD4 T cells and may be the result of oxygen radical damage to the grafted B cells. Preliminary evidence indicates that the disease process can be controlled by oxygen radical scavengers (superoxidedisputase and catalase). Work in this area will be expanded to define the effect of these enzymes both in combination and separately, on the natural history of disease recurrence in the grafted tissue. There is still uncertainty concerning the susceptibility of allogeneic islet tissue to disease recurrence in the spontaneously diabetic BB rat. The present data suggests that difference reported by different laboratories may reflect differences in sensitivity of islet tissue to the disease process. The grafting of islet tissue from a number of different allogeneic strains to spontaneously diabetic BB rats will be used to define and investigate this problem in greater depth.